Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-l-Ribitol Pyrophosphorylase A Muscular Dystrophy

  • Clin Chem. 2019 Oct;65(10):1295-1306. doi: 10.1373/clinchem.2019.305391.
Walinka van Tol  1  2 ,  Monique van Scherpenzeel  2 ,  Mohammad Alsady  1 ,  Moniek Riemersma  1 ,  Esther Hermans  1 ,  Else Kragt  2 ,  Giorgio Tasca  3 ,  Erik-Jan Kamsteeg  4 ,  Maartje Pennings  4 ,  Ellen van Beusekom  4 ,  Jeroen R Vermeulen  5 ,  Hans van Bokhoven  4 ,  Nicol C Voermans  1 ,  Michèl A Willemsen  6 ,  Angel Ashikov  1 ,  Dirk J Lefeber  7  2
Affiliations
  • 1. Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 2. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 3. Unità Operativa Complessa di Neurologia, Dipartimento di Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico A. Gemelli IRCCS, Roma, Italy.
  • 4. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 5. Department of Child Neurology, VUmc, Amsterdam, the Netherlands.
  • 6. Department of Pediatric Neurology, Amalia Children's Hospital, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 7. Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; [email protected].
PMID: 31375477 DOI: 10.1373/clinchem.2019.305391
Abstract

Background: Many muscular dystrophies currently remain untreatable. Recently, dietary ribitol has been suggested as a treatment for cytidine diphosphate (CDP)-l-ribitol pyrophosphorylase A (CRPPA, ISPD), fukutin (FKTN), and fukutin-related protein (FKRP) myopathy, by raising CDP-ribitol concentrations. Thus, to facilitate fast diagnosis, treatment development, and treatment monitoring, sensitive detection of CDP-ribitol is required.

Methods: An LC-MS method was optimized for CDP-ribitol in human and mice cells and tissues.

Results: CDP-ribitol, the product of CRPPA, was detected in all major human and mouse tissues. Moreover, CDP-ribitol concentrations were reduced in fibroblasts and skeletal muscle biopsies from patients with CRPPA myopathy, showing that CDP-ribitol could serve as a diagnostic marker to identify patients with CRPPA with severe Walker-Warburg syndrome and mild limb-girdle muscular dystrophy (LGMD) phenotypes. A screen for potentially therapeutic Monosaccharides revealed that ribose, in addition to ribitol, restored CDP-ribitol concentrations and the associated O-glycosylation defect of α-dystroglycan. As the effect occurred in a mutation-dependent manner, we established a CDP-ribitol blood test to facilitate diagnosis and predict individualized treatment response. Ex vivo incubation of blood cells with ribose or ribitol restored CDP-ribitol concentrations in a patient with CRPPA LGMD.

Conclusions: Sensitive detection of CDP-ribitol with LC-MS allows fast diagnosis of patients with severe and mild CRPPA myopathy. Ribose offers a readily testable dietary therapy for CRPPA myopathy, with possible applicability for patients with FKRP and FKTN myopathy. Evaluation of CDP-ribitol in blood is a promising tool for the evaluation and monitoring of dietary therapies for CRPPA myopathy in a patient-specific manner.

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